Homeostatic signaling systems are ubiquitous throughout biology. By definition, homeostasis refers to the ability of a cell or system of cells t respond to a perturbation and maintain a constant physiology. This concept has been applied to the system level control of blood pressure and heart rate as well as cellular physiological systems including control of glucose and intracellular calcium4. It is now apparent that evolutionarily conserved homeostatic signaling systems have evolved to stabilize the excitable properties of nerve and muscle4. Despite the hypothesized importance of the homeostatic signaling systems that control cellular excitation, very little is known about the underlying molecular mechanisms. In a large-scale forward genetic screen the Davis laboratory has identified mutations in the Drosophila multiplexin (dmp) gene, encoding an extracellular matrix protein, that blocks the homeostatic regulation of synaptic transmission, termed 'synaptic homeostasis'. Intriguingly, this extracellular matrix protein specifically regulates synaptic homeostasis without changing synapse morphology during development. Thus, it can potentially function as the retrograde signaling molecule that modulates presynaptic neurotransmitter release upon perturbations of postsynaptic receptor function. Studying the function of the dmp gene would significantly advance our knowledge of the molecular mechanisms of synaptic homeostasis, an evolutionarily conserved process that occurs at the NMJ of organisms ranging from Drosophila to humans. Importantly, the dmp gene has vertebrate homologues that are expressed in cardiac muscles and nervous system29, potentially serving a conserved function to maintain the appropriate excitable properties of nerve and muscle. Unraveling the function of extracellular matrix proteins in synaptic transmission and homeostatic plasticity could, therefore, be a critical step in developing new treatments for collagen-related neurological diseases. PUBLIC HEALTH RELEVANCE: Neural systems maintain a constant output in the face of changing inputs: too little activity of brain cells disrupts their ability to communicate; too much activity leads to over-excitation and epilepsy or migraines, diseases which affect over 10% of the population. A few genes have been previously shown to be involved in the cellular processes controlling the excitability and stability, but how they work together remains unknown. We propose to characterize a gene which exists in flies and in humans. It appears to be an inter-cellular signal connecting other disparate signals. The characterization of this gene will open the door to many new treatments for diseases of neuronal over-activity.